Monday, March 16, 2015

In these days of irrational exuberance about neural circuit models, it's wise to remember the limitations of current deep brain stimulation (DBS) methods to treat psychiatric disorders. If you recall (from Dec. 2013), Neurotech Business Report revealed that "St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression..."

A recent comment on my old post about the BROADEN Trial1 had an even more pessimistic revelation: there was only a 17.2% chance of a successful study outcome:

Regarding Anonymous' comment on January 30, 2015 11:01 AM, as follows in part:"Second, the information that it failed FDA approval or halted by the FDA is prima facie a blatant lie and demonstratively false. St Jude, the company, withdrew the trial."

Much of this confusion could be cleared up if the study sponsors practiced more transparency.A bit of research reveals that St. Judes' BROADEN study was discontinued after the results of a futility analysis predicted the probability of a successful study outcome to be no greater than 17.2%. (According to a letter from St. Jude)

Medtronic hasn't fared any better. Like the BROADEN study, Medtronics' VC DBS study was discontinued owing to inefficacy based on futility Analysis.

If the FDA allowed St. Jude to save face with its shareholders and withdraw the trial rather than have the FDA take official action, that's asserting semantics over substance.

A multicenter, prospective, randomized trial of SCC DBS for severe, medically refractory MDD (the BROADEN study), sponsored by St. Jude Medical, was recently discontinued after the results of a futility analysis (designed to test the probability of success of the study after 75 patients reached the 6-month postoperative follow-up) statistically predicted the probability of a successful study outcome to be no greater than 17.2 % (letter from St. Jude Medical Clinical Study Management).

I (and others) had been looking far and wide for an update on the BROADEN Trial, whether in ClinicalTrials.gov or published by the sponsors. Instead, the authors of an outside review article (who seem to be involved in DBS for movement disorders and not depression) had access to a letter from St. Jude Medical Clinical Studies.

Despite the very encouraging outcomes reported in the open-label studies described above, a recent multicenter, prospective, randomized trial of VC/VS DBS for MDD sponsored by Medtronic failed to show significant improvement in the stimulation group compared with a sham stimulation group 16 weeks after implantation of the device. This study was discontinued owing to perceived futility, and while investigators remain hopeful that modifications of inclusion criteria and technique might ultimately result in demonstrable clinical benefit in some cohort of severely debilitated, medically refractory patients with MDD, no studies investigating the efficacy of VC/VS DBS for MDD are currently open.

There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.

Additional studies (with different stimulation parameters, better target localization, more stringent subject selection criteria) are needed, one would say. Self-reported outcomes from the patients themselves range from “...the side effects caused by the device were, at times, worse than the depression itself” to “I feel like I have a second chance at life.”

UPDATE to the update (March 22 2015): The Vancouver Sun reported (on 3/17/2015) that the sponsor ended the trial:

A procedure that treats depression by using electrodes implanted deep
in the brain won’t be available to the public soon, says the researcher
who pioneered the procedure more than a decade ago with a team at the University of Toronto.

Neurologist Dr. Helen Mayberg,
now at Emory University in Atlanta, said in Vancouver Tuesday that 80
per cent of her recent patients find sustained relief from severe
depression after fine wires are surgically implanted to deliver
electrical current to a specific part of the brain.

But a medical
equipment maker halted its tests to commercialize the discovery six
months after implanting devices in 125 recruits in 2013.

Data from
that work has not yet been released by St. Jude Medical Inc. based in
St. Paul, Minn., although a spokesman for the company said Tuesday that
it will be made public. The patients still have the implanted devices
and the study was not stopped for safety reasons.

In the initial BuzzFeed poll, 75% saw it as white and gold, rather than the actual colors of blue and black. Facebook's more systematic research estimated this number was only 58% (and influenced by probably exposure to articles that used Photoshop). Facebook also reported differences by sex (males more b/b), age (youngsters more b/b), and interface (more b/b on computer vs. iPhone and Android).

Dr. Cedar Riener wrote two informativeposts about why people might perceive the colors differently, but Dr. Bell was not satisfied with this and other explanations. Wired consulted two experts in color vision:

“Our visual system is supposed to throw away information about the illuminant and extract information about the actual reflectance,” says Jay Neitz, a neuroscientist at the University of Washington. “But I’ve studied individual differences in color vision for 30 years, and this is one of the biggest individual differences I’ve ever seen.”

and

“What’s happening here is your visual system is looking at this thing, and you’re trying to discount the chromatic bias of the daylight axis,” says Bevil Conway, a neuroscientist who studies color and vision at Wellesley College. “So people either discount the blue side, in which case they end up seeing white and gold, or discount the gold side, in which case they end up with blue and black.”

Finally, Dr. Conway threw out the chronotype card:

So when context varies, so will people’s visual perception. “Most people will see the blue on the white background as blue,” Conway says. “But on the black background some might see it as white.” He even speculated, perhaps jokingly, that the white-gold prejudice favors the idea of seeing the dress under strong daylight. “I bet night owls are more likely to see it as blue-black,” Conway says.

Recent research suggests that ipRGCs may play more of a role in visual perception than was originally believed. As Vaughan said, melanopsin (the photopigment in ipRGCs) is involved in brightness discrimination and is most sensitive to blue light. Brown et al. (2012) found that melanopsin knockout mice showed a change in spectral sensitivity that affected brightness discrimination; the KO mice needed higher green radiance to perform the task as well as the control mice.

The figure below shows the spectra of human cone cells most sensitive to Short (S), Medium (M), and Long (L) wavelengths.

The peak spectral sensitivity for melanopsin photoreceptors is in the blue range. How do you isolate the role of melanopsin in humans? Brown et al. (2012) used metamers, which are...

...light stimuli that appear indistinguishable to cones (and therefore have the same color and photopic luminance) despite having different spectral power distributions. ... to maximize the melanopic excitation achievable with the metamer approach, we aimed to circumvent rod-based responses by working at background light levels sufficiently bright to saturate rods.

They verified their approach in mice, then used a four LED system to generate stimuli that diffed in presumed melanopsin excitation, but not S, M, or L cone excitation. All six of the human participants perceived greater brightness as melanopsin excitation increased (see Fig. 3E below). Also notice the individual differences in test radiance with the fixed 11% melanopic excitation (on the right of the graph).

Modified from Fig. 3E (Brown et al. (2012). Across six subjects, there was a strong correlation between the test radiance at equal brightness and the melanopic excitation of the reference stimulus (p < 0.001).1

Maybe Team white/gold and Team blue/black differ on this dimension? And while we're at it, is variation in melanopsin related to circadian rhythms, chronotype, even seasonal affective disorder (SAD)? 2 There is some evidence in favor of the circadian connections. Variants of the melanopsin (Opn4) gene might be related to chronotype and to SAD, which is much more common in women. Another Opn4 polymorphism may be related to pupillary light responses, which would affect light and dark adaptation. These genetic findings should be interpreted with caution, however, until replicated in larger populations.

A recent method developed by Cao, Nicandro and Barrionuevo (2015) increases the precision of isolating ipRGC function in humans. The four-primary photostimulator used by Brown et al. (2012) assumed that the rod cells were saturated at the light levels they used. However, Cao et al. (2015) warn that “a four-primary method is not sufficient when rods are functioning together with melanopsin and cones.” So they:

...introduced a new LED-based five-primary photostimulating method that can independently control the excitation of melanopsin-containing ipRGC, rod and cone photoreceptors at constant background photoreceptor excitation levels.

Their Journal of Vision article is freely available, so you can read all about the methods and experimental results there (i.e., I'm not even going to try to summarize them here).

So the question remains: beyond the many perceptual influences that everyone has already discussed at length (e.g., color constancy, Bayesian priors, context, chromatic bias, etc.), could variation in ipRGC responses influence how you see “The Dress”?

Footnotes

1Fig 3E (continued). The effect was unrelated to any impact of melanopsin on pupil size. Subjects were asked to judge the relative brightness of three metameric stimuli (melanopic contrast −11%, 0%, and +11%) with respect to test stimuli whose spectral composition was invariant (and equivalent to the melanopsin 0% stimulus) but whose radiance changed between trials.

2This would test Conway's quip that night owls are more likely to see the dress as blue and black.

3Aguirre also said that a contribution from melanopsin (to the dress effect) was doubtful,
at least from any phasic effect: “It's a slow signal with poor spatial
resolution and subtle perceptual effects.” It remains to be seen whether
any bias towards discarding blue vs. yellow illuminant information is affected by chronotype.

The opposition of the S cones is revealed in a seemingly paradoxical dilation of the pupil to greater S-cone photon capture. This surprising result is explained by the neurophysiological properties of ipRGCs found in animal studies.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.